Methods for preparing 7-(2'-substituted-beta-D-ribofuranosyl)-4-(NR2R3)-5-(substituted ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine derivatives

• US 20050215510A1
• Filed: 10/20/2004
• Published: 09/29/2005
• Est. Priority Date: 10/27/2003
• Status: Active Grant

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Genelabs Technologies, Inc. (GlaxoSmithKline PLC)
• Inventors: Roberts, Christopher D., Dyatkina, Natalia B., Keicher, Jesse D.
• Granted Patent: US 7,169,918 B2
• Time in Patent Office: Days
• US Class Current: 514/45
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals

Abstract

Disclosed are methods and intermediates for the preparation of 7-(2′-R¹-substituted-β-D-ribofuranosyl)-4-amino-5-(optionally substituted ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine compounds. These compounds are useful in treating viral infections caused by a flaviviridae family virus, such as hepatitis C virus.

Claims

1. A method for preparing 7-(2′

-R¹-substituted-β

-D-ribofuranosyl)-4-(NR²R³)-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula I;

2. The method according to claim 1 wherein R¹ is alkyl.

3. The method according to claim 2 wherein R¹ is methyl.

4. The method according to claim 1 wherein R² and R³ are independently selected from hydrogen, alkyl, amino, substituted amino and hydroxy.

5. The method according to claim 4 wherein R² and R³ are hydrogen.

6. The method according to claim 4 wherein R² is hydrogen and R³ is hydroxy.

7. The method according to claim 4 wherein R² is hydrogen and R³ is amino or alkyl substituted amino.

8. The method according to claim 1 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-riboftiranose is 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose.

9. The method according to claim 1 wherein the 4,5-dihalo-7H-pyrrolo[2,3-d]pyrimidine is 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine.

10. The method according to claim 1 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose by contacting with HBr.

11. A method for the synthesis of 7-(2′

-R¹-substituted-β

-D-ribofuranosyl)-4-(NR²R³)-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula I;

12. The method according to claim 11 wherein R¹ is alkyl.

13. The method according to claim 12 wherein R¹ is methyl.

14. The method according to claim 11 wherein R² and R³ are independently selected from hydrogen, alkyl, amino, substituted amino and hydroxy.

15. The method according to claim 14 wherein R² and R³ are hydrogen.

16. The method according to claim 14 wherein R² is hydrogen and R³ is hydroxy.

17. The method according to claim 14 wherein R² is hydrogen and R³ is amino or alkyl substituted amino.

18. The method according to claim 11 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose.

19. The method according to claim 11 wherein the 4,5-dihalo-7H-pyrrolo[2,3-d]pyrimidine is 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine.

20. The method according to claim 11 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose by contacting with HBr.

21. A method for the synthesis of 7-(2′

-R¹-substituted-β

-D-ribofuranosyl)-4-(NR²R³)-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula I;

22. The method according to claim 21 wherein R¹ is alkyl.

23. The method according to claim 22 wherein R¹ is methyl.

24. The method according to claim 21 wherein R² and R³ are independently selected from hydrogen, alkyl, amino, substituted amino and hydroxy.

25. The method according to claim 24 wherein R² and R³ are hydrogen.

26. The method according to claim 24 wherein R is hydrogen and R³ is hydroxy.

27. The method according to claim 24 wherein R is hydrogen and R³ is amino or alkyl substituted amino.

28. The method according to claim 21 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose.

29. The method according to claim 21 wherein the 4,5-dihalo-7H-pyrrolo[2,3-d]pyrimidine is 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine.

30. The method according to claim 21 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose by contacting with HBr.

31. A method for the synthesis of 7-(2′

-R¹-substituted-β

-D-ribofuranosyl)-4-(NR²R³)-5-(2-substituted ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula II;

32. The method according to claim 31 wherein R¹ is alkyl.

33. The method according to claim 32 wherein R¹ is methyl.

34. The method according to claim 31 wherein R² and R³ are independently selected from hydrogen, alkyl, amino, substituted amino and hydroxy.

35. The method according to claim 34 wherein R² and R³ are hydrogen.

36. The method according to claim 34 wherein R² is hydrogen and R³ is hydroxy.

37. The method according to claim 34 wherein R² is hydrogen and R³ is amino or alkyl substituted amino.

38. The method according to claim 31 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose.

39. The method according to claim 31 wherein the 4,5-dihalo-7H-pyrrolo[2,3-d]pyrimidine is 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine.

40. The method according to claim 31 wherein the 1-bromo-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-protected-2-R¹-substituted-D-ribofuranose by contacting with HBr.

41. The method according to claim 31 wherein R is selected from the group consisting of phenyl, diethoxy acetal, carboxy, amido, and ethoxycarbonyl.

42. A method for the synthesis of 7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula III;

43. The method according to claim 42 wherein the 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuiranose by contacting with HBr.

44. A method for the synthesis of 7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula III;

45. The method according to claim 44 wherein the 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose by contacting with HBr.

46. A method for the synthesis of 7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine of formula III;

47. The method according to claim 46 wherein the 1-bromo-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose is formed in situ from the 1-methoxy-3,5-di-O-(2,4-dichlorobenzyl)-2-methyl-D-ribofuranose by contacting with HBr.

48. A compound of formula IV:

49. The compound according to claim 48 wherein Pg² is H, and Pg and Pg¹ are the same hydroxy protecting groups.

50. The compound according to claim 49 wherein Pg and Pg¹ are 2,4-dichlorobenzyl.

51. A compound selected from the group consisting of:

7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(trimethylsilanylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (7);

7-(2′

-methyl-β

-D-ribofuranosyl)-4-chloro-5-(trimethylsilanylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (10);

7-(2′

-methyl-β

-D-ribofuranosyl)-4-chloro-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (16);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-chloro-5-(trimethylsilanylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (7a);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-chloro-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (15);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofaranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (14);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(trimethylsilanylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (13);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(2-(diethoxy acetal)-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (17a);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(2-amido-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (17b);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(2-carboxy-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (17c);

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(2-ethoxycarbonyl-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (17d); and

7-(2′

-methyl-3′

,5′

-di-O-(2,4-dichlorobenzyl)-β

-D-ribofuranosyl)-4-amino-5-(2-phenyl-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine (17e).

52. A compound of formula V:

53. A compound selected from the group consisting of:

4-chloro-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

4-chloro-5-(trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine; and

4-chloro-5-(phenylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine.

54. A compound of formula VI:

55. A compound selected from the group consisting of:

4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

4-amino-5-(trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine; and

4-amino-5-(phenylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine.